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An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
Published on: September 12, 2019
WZ4003 sensitizes hepatocellular carcinoma to OSI-027 by inhibiting ARK5-mediated autophagy
Bryan Wei Chen1, Jie-Ni Xiong2, Xiao Zhi1
1Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Abstract:
Mammalian target of rapamycin kinase inhibitors (mTOR-KIs) represent a novel promising treatment option for cancer therapy. OSI-027, a typical mTOR-KI, has been confirmed to suppress the proliferation of hepatocellular carcinoma (HCC) in preclinical models. However, mTOR-KIs confer limited therapeutic response against HCC, and the underlying mechanism remains enigmatic. The present study aimed to reveal the interaction between NUAK inhibitor WZ4003 and OSI-027 in HCC. Treatment with OSI-027 was found to result in up-regulation of ARK5 (also known as NUAK1), whereas both ARK5 knockdown and WZ4003 sensitized HCC cells to OSI-027. Intriguingly, knockdown of ARK5 abrogated the synergistic anti-HCC effect observed with the combination of WZ4003 and OSI-027. Additionally, OSI-027 triggered autophagy, an effect that could be reversed by WZ4003. Furthermore, WZ4003 was found to regulate autophagy in an ARK5-dependent manner, and phosphorylation of unc-51 like autophagy activating kinase 1 (ULK1) at Ser757 served as a downstream effector of ARK5. Notably, both chloroquine treatment and ULK1-S757E transfection abolished the OSI-027/WZ4003 synergy. We also confirmed a synergism pattern between OSI-027 and WZ4003 in an HCC xenograft model. Moreover, elevated ARK5 expression was observed in HCC specimens and was independently associated with an unfavorable recurrence-free survival (RFS). Our findings propose a novel strategy for augmenting sensitivity to OSI-027 in HCC, further underscoring the significance of ARK5 and autophagy as cancer therapeutic targets.
Insights
This study reveals that combining the NUAK inhibitor WZ4003 with the mTOR kinase inhibitor OSI-027 enhances hepatocellular carcinoma (HCC) treatment. Targeting ARK5 and autophagy offers a novel strategy to improve HCC therapy efficacy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Mammalian target of rapamycin kinase inhibitors (mTOR-KIs) show promise in cancer therapy, including hepatocellular carcinoma (HCC).
- However, the therapeutic efficacy of mTOR-KIs against HCC is limited, and the underlying mechanisms are not fully understood.
- Understanding drug interactions is crucial for developing effective cancer treatments.
Purpose of the Study:
- To investigate the interaction between the NUAK inhibitor WZ4003 and the mTOR-KI OSI-027 in HCC.
- To elucidate the role of ARK5 (NUAK1) and autophagy in the synergistic effects of WZ4003 and OSI-027.
- To identify potential therapeutic targets for improving HCC treatment response.
Main Methods:
- Treatment of HCC cells and xenograft models with OSI-027 and/or WZ4003.
- Assessment of cell proliferation, autophagy, and protein phosphorylation.
- Genetic manipulation, including ARK5 knockdown and ULK1 phosphorylation site mutation.
- Analysis of ARK5 expression in HCC patient specimens.
Main Results:
- OSI-027 treatment upregulated ARK5 expression in HCC cells.
- Both WZ4003 and ARK5 knockdown sensitized HCC cells to OSI-027, indicating a synergistic effect.
- Knockdown of ARK5 abolished the synergistic anti-HCC effect of the WZ4003/OSI-027 combination.
- OSI-027 induced autophagy, which was reversed by WZ4003 in an ARK5-dependent manner.
- Phosphorylation of ULK1 at Ser757 was identified as a downstream effector of ARK5 in autophagy regulation.
- Synergistic effects were confirmed in an HCC xenograft model.
- Elevated ARK5 expression in HCC tissues correlated with unfavorable recurrence-free survival.
Conclusions:
- Combining WZ4003 with OSI-027 demonstrates a synergistic anti-HCC effect.
- The interaction involves ARK5-mediated regulation of autophagy via ULK1 phosphorylation.
- Targeting ARK5 and modulating autophagy present a novel therapeutic strategy to enhance sensitivity to mTOR-KIs in HCC.
- Elevated ARK5 expression serves as a potential prognostic biomarker for HCC.
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